Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine and threonine residues of proteins. The phosphorylation of proteins modulates various cell activities such as cell growth, differentiation and proliferation. Abnormal PK activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma.
Numerous attempts have been made to modulate PK activity. Examples are: biomimetic approaches using large molecules patterned on those involved in the actual cellular processes (e.g., mutant ligands (U.S. Pat. No. 4,966,849)); soluble receptors and antibodies (WO 94/10202, Kendall et al., Proc. Nat'l Acad. Sci. 90: 10705-09 (1994), Kim et al., Nature 362: 841-844 (1993)); RNA ligands (Jelinek et al., Biochemistry 33: 10450-56); Takano et al., Mol. Bio. Cell 4: 358A (1993); Kinsella et al., Exo. Cell Res. 199: 56-62 (1992); Wright et al., J. Cellular Phys. 152: 448-57); and tyrosine kinase inhibitors (WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808; U.S. Pat. No. 5,330,992; Mariani et al., Proc. Am. Assoc. Cancer Res. 35: 2268 (1994)). Despite such attempts, a need still exists for effective methods of modulating PK activity.